17-mono esters of corticoids



United States Patent 3,422,193 17-MON0 ESTERS 0F CORTICOIDS Elliot L.Shapiro, Cedar Grove, Elliott J. Collins, Mendham, and Lawrence E.Finckenor, Wayne, N.J., as-

signors to Schering Corporation, Bloomfield, N.J., a

corporation of New Jersey No Drawing. Filed Aug. 11, 1966, Ser. No.571,721 U.S. Cl. 424-243 9 Claims Int. Cl. A61k 25/00; C07c 169/36ABSTRACT OF THE DISCLOSURE This invention relates to novel16u-methyl-6a(X),9a, 1lfl-dichloro-1,4-pregnadiene17a,2l-diol-3,20-dione 17- lower alkanoates wherein X is a memberselected from the group consisting of hydrogen, fluoro, chloro andmethyl; and to methods for preparing and using said compounds incorticoid antiinflammatory therapy.

This invention relates to new compositions of matter classifiable in thefield of steroid chemistry as l7a-lower alkanoate esters of16a-methyl-9a,11;8-dihalo corticoids, to certain 6a-substitutedderivatives thereof, and to the use of these compounds in the form ofpharmaceutical formulations in the application of corticoidantiinflammatory therapy.

In one of its composition aspects the instant invention may be describedas residing in the concept of a steroid compound having the molecularstructure of 160L-II16thy1- 9a,1lfi-dichloro-1,4-pregnadiene 1711,21diol-3,20-dione 17-lower alkanoate and 6a-fluoro-, 6a-ch1oroand60amethylderivatives thereof.

In another or its composition aspects the instant invention may bedescribed as residing in the concept of a pharmaceutical formulation,containing as the essential active ingredient a tangible embodiment asdescribed above.

In its process aspect this invention may be described as residing in theconcept of a method of treating inflammatory conditions by theutilization of pharmaceutical formulations containing dosage units ofthe tangible embodiments of this invention.

The instant inveniton is based upon the discovery that the tangibleembodiments disclosed herein elicit a potent antiinfiammatory eflect andmore specifically on the discovery that these embodiments elicit asustained antiinflammatory effect upon oral administration to mammalsand in particular, domestic animals.

The novel compounds of the instant invention may be represented as amember of the group consisting of 1,4-pregnadienes having the followingstructural formula:

CH2OH wherein X is a member selected from the group hydrogen, fluorine,chlorine and methyl and R is lower alkyl. Lower alkyl being definedherein as saturated hydrocarbon radicals being either straight orbranched chain, having 2 to 4 carbon atoms. Therefore, as defined, thegrouping at position 17 form esters such as propionate,

ice

butyrate, isobutyrate, valerate, 2'-methylbutyrate and isovalerate.

The tangible embodiments of this invention may be prepared as describedin the following general procedures, it being understood that theseprocedures are of general applicability and may be used to prepare thetangible embodiments having any of the designated substituents atpositions 6 and 17.

A 16a-methyl-6a-X,9a,11.}8 dichloro-1,4-pregnadiene-17a,21-diol-3,20-dione '(II) is reacted with a mixture of lower alkanoicacid, butyric acid for example, and trifluoroacetic anhydride at aboutfor about 1 hour. The,17,21-dibutyrate product, III, is subsequentlysubjected to a selective acid hydrolysis to yield the 17amonoesterembodiment. The hydrolysis is usually effected by the utilization ofaqueous perchloric acid in a nonreactive water miscible organic solvent.This esterification and selective hydrolysis is depicted as follows:

Alternatively, by treating II with a tri-loweralk-yl orthoester of alower alkanoic acid, trimethyl orthobutyrate for example, in thepresence of a strong acid catalyst and a suitable nonhydroxylatedorganic solvent, the steroidal 17,21-methyl orthobutyrate, IV, isobtained. Mild hydrolysis of the steroidal orthoester in the presence ofa weak acid, such as in an aqueous acetic acid medium, converts it tothe 17a-monobutyrate embodiment. The 17u-ester can be isolated by waterprecipitation or by dilution with water followed by extraction with awater immiscible solvent and recovery therefrom.

CH2O OB. L o-(oHmcrn o l/ 01f "CH; E l II a] R=OH1 I An additionalprocedure is that whereby II is converted to a 21-acetate V via artknown techniques and the 21- acetate acylated at the 17-position with alower alkanoic acid in combination with trifluoroacetic anhydride asanalogously described heretofore, yielding the 17-lower alkanoate2l-acetate, VI. The Zl-acetate function can be selectively removed bythe aqueous perchloric acid technique described above.

ll CHzO C CH3 $1120 i l CH3 In the foregoing procedures R and X are asdefined hereinbefore.

As used herein the term strong acid catalyst denotes such acids asp-toluenesulfonic acid, methanesulfonic acid or mineral acid asrepresented by perchloric or sulfuric acids. The term nonreactive watermiscible organic solvent is meant to denote those solvents which areessentially inert to the reactants under the conditions utilized.Exemplary of such solvents are methanol, ethanol, dioxane,tetrahydrofuran and the like with methanol being the preferred solvent.The term suitable nonhydroxylated organic solvent as used herein meanssuch solvents as benzene, toluene, dimethylsulfoxide, dimethylformamide,N-methyl pyrollidone and the like. Benzene is the solvent mostfrequently used for the orthoester formation, although the othersolvents indicated may advantageously be used with starting materialshaving a low order of solubility in benzene.

The tangible embodiments of this invention elicit a potentantiinfiammatory effect generally several times greater than theirrespective 17a-hydroxy analogs. They possess the unusual quality ofeliciting an enhanced response as tested in dogs via the oral route.Further the embodiments manifest a sustained antiinfiammatory activitythrough a 24 hour period after a single oral therapeutic dose.Significantly, the tangible embodiments give this prolongation ofactivity without sacrificing immediacy of response. Results fromparallel tests, utilizing both the parent alcohols and the 170z-10WCIalkanoate embodiments, indicate an absence of time differential in theonset of eosinopenia between the various forms. The l7u-lower alkanoateembodiments, however, elicit an eosinopenic response long after that ofthe hydroxy analogs has ceased. It is generally recognized that aneosinopenic response can be normally associated with effective corticoidanti inflammatory therapy and is often used as an empirical gauge ofantiinfiammatory activity.

In addition to the tangible embodiments being longer acting than theirrespective 1704,21-dll counterparts, they are longer acting thanprednisolone 2l-acetate. Under controlled laboratory conditions, dogsgiven a single oral therapeutic dose of16a-methyl-9a,1lfi-dichloro-lA-pregnadiene-l7u,2l-diol-3,20-dionel7-butyrate exhibited an antiinflammatory response of longer durationthan those given 10 times the therapeutic dose of prednisolone acetate.These embodiments also exhibit a more pronounced and sustained oralactivity than do their 16- desmethyl analogs. In fact, the tangibleembodiments of the instant invention are unique in their ability toelicit such a response after a single oral therapeutic dose.

The high potency of these embodiments coupled with their sustainedaction permits the attainment and maintenance of an adequateantiinflammatory action on a minimal dosage thereby maximizing therelief being derived, while minimizing the probability of thedevelopment of undesirable side effects.

The compounds disclosed herein in the form of pharmaceuticalformulations, as will be described hereinafter, and by virtue of theirunique prolonged activity, are eminently suited for the treatment ofcollagen diseases on an intermittent dosage regimen.

The following examples are set forth to further illustrate theprocedures employed in preparing the compounds of this invention.

Preparation of starting materials (A) Dissolve 6.0 g. of6ot-fiuoro-l6u-methyl-1,4-pregnadiene-l 1;3,17a,2 l-triol-3,20-dione21-acetate in 30 ml. of dimethylformamide and 30 ml. of pyridine. Heatthe solution to add 5.0 ml. of methanesulfonyl chloride and maintain at80 for 1 hour. Add a few pieces of ice to the mixture, then precipitatethe product by pouring the reaction mixture into vigorously stirred icewater. Wash the precipitate with water, dry the product and crystallizefrom acetone-hexane obtaining 6ot-fil10l'O-16umethyl 1,4,9(11)pregnatriene l7a,2l-diol-3,20-dione 2l-acetate.

(B) Dissolve 4.12 g. of 6 Z-fluOI'O-16lX-II1thyl-1,4,9 (l1) pregnatriene17a,21-diol-3,20-dione 2l-acetate in 200 ml. of methylene chloridecontaining 4.0 ml. of pyridine. Add a solution containing 760 mg. ofchlorine in 14.7 ml. of carbon tetrachloride to the steroid solution atl5. Maintain the reaction mixture at 15 for 30 minutes then allow thesolution to warm up to room temperature. Wash the solution sequentiallywith water, dilute acid and water. Dry the solution over anhydrousmagnesium sulfate and reduce its volume, concomitantly, adding hexane togive a thick crystal slurry. Cool the slurry to 0 and hold for 1 hour.Filter and wash the product with hexane. Recrystallize from acetone toobtain 6a fluoro 16a-methyl-9a,1lB-dichloro-1,4-pregnadiene-17u.2l-diol-3.20-di0ne 2l-acetate.

(C) Dissolve 150 mg. of the product from above in 10 ml. of methanol and0.27 ml. of 70% perchloric acid. Permit the reaction mixture to remainat room temperature for 18 hours. Add 100 ml. of a 5% salt solution andextract the product with methylene chloride. Wash the extract with a 5%solution of sodium carbonate and with water. Dry the extract overanhydrous magnesium sulfate, filter and concentrate the filtrate to acrystal slurry. Chill the slurry to 0 and hold overnight. Filter andwash the crystalline product sparingly with ethyl ether. Dry the6a-fluoro-l6a-methyl :,11/3 dichloro-1,4-pregnadiene-17u,2l-diol-3,20-dione at 60.

In like manner, the above procedure may be used on the appropriately6a-substituted starting materials to prepare:

EXAMPLE 1 l6a-methyl-9a,l 1 fit-dichloro-1,4-pregnadiene-17a,2l-diol-3,20-dine 17-propionate Dissolve 8.5 g. ofl6a-methyl-9a,lIB-dichloro-lA-pregnadiene-l7a,2l-diol-3,20-dione inpropionic acid (85 ml.). Add trifiuoroacetic anhydride (30 ml.) withstirring and heat the mixture to 80 on a steam bath. Continue heatingand stirring for 1 hour. Cool the mixture to 50 and add 25 ml. water.Stir for 10 minutes to allow the anhydride to hydrolyze. Cool thereaction mixture to room temperature and pour slowly into 850 ml. ofvigorously stirred ice water. Extract the product with 350 ml. ofmethylene chloride. Wash the methylene chloride solution sequentiallywith water, sodium bicarbonate solution and water until the washes areneutral. Dry the extract over anhydrous magnesium sulfate, filter andconcentrate to a residue. Dissolve the residue in ethyl acetate andcrystallize to obtain 16a-methyl-9a,1lfi-dichloro-1,4-pregnadiene-17a,21-diol-3,20-dione 17,21-dipropionate.

Dissolve 5 g. of the dipropionate prepared above in 350 ml. methylalcohol and add 9.0 ml. 70% perchloric acid. Stir the mixture at roomtemperature overnight (18 hours) and dilute the solution with 5 volumesof salt water. Extract the product with methylene chloride, wash theextract with water, a 5% aqueous sodium bicarbonate solution and finallywith water until the washes are neutral. Dry the organic solvent layerover magnesium sulfate, filter and concentrate filtrate to a residue.Dissolve the residue in ethyl acetate at reflux. Filter the hotsolution, concentrate to a crystal slurry and cool to 5. Filter thecrystalline suspension to obtain16a-methyl-9u,11[3-dichloro-1,4-pregnadiene-l7a,21-diol-3,20-dione17-propionate.

In like manner by employing the appropriately 6u-substituted steroid 1704,21-di0l starting material, by using the process of this example andthe appropriate loweralkanoic acid the following embodiments areprepared:

16a-methyl-9u,l 1 fi-dichloro- 1,4-pregnadiene- 17zx,2 l-diol-3,20-dione l7-butyrate 16a-methyl-9 u,1LB-dichloro-1,4-pregnadiene-17a,2l-diol- 3,20-dione 17-isobutyrate16ot-I116thyl-9u,1 l 3-dichlorol,4-pregnadiene-l7a,2 1 -diol- 3,20-dione17-valerate 16a-methyl-9a,1Iii-dichloro-1,4-pregnadiene-17a,2l-diol-3,20-dione l7-isovalerate l6a-methyl-9 11,1 1 fl-dichloro- 1,4-pregnadiene- 17a,2 l-diol- 3,20-dione 17- (2'-methylbutyrate)6a,16a-dimethyl-9o,1lei-dichloro-1,4-pregnadiene-170:,21-

diol-3,20-dione l7-butyrate 61x, 1 6a-dimethyl-9 a, 1 lfi-dichloro-1,4-pre gnadiene-l7a,2 1-

diol-3,20-dione 17-valerate 6a,l6a-dimethyl-9a,l l3-dichloro-1,4-pregnadiene-l7a,21-

dio13,20-dione 17-isobutyrate 6a,16ot-dimeh)1-9a,1lfl-dichloro-l,4-pregnadiene-l7a,2l-

diol-3,20-dione 17-isovalerate 6a, 1 6a-dimethyl-9a, l 1 fl-dichloro- 1,4-pregnadiene-17u,2 1-

diol-3,20-dione 17 (2-methylbutyrate) l6ot-methyl-6a,9u,1 l3-trichloro-1,4-pregnadiene-170:,21-

diol-3,20-dione l7-propionate 16oc-m6thy16a,90c,1 lfi-trichloro- 1,4-pregnadiene- 17a,2 1-

diol3,20-dione l7-butyrate16a-methyl-6a,9u,1IB-trichloro-1,4-pregnadiene-170:,21-

diol-3,20-dione 17-isobutyratel6a-methyl-6a,9a,1lfl-trichloro-1,4-pregnadiene-17a,21-

diol-3 ,20-dione 17 -valerate16a-methyl-6a,9a,1lfi-trichloro-1,4-pregnadiene-17a,2l-

diol-3,20-dione 17-isovalerate l6a-rnethyl-6a,9a,1 1 ,B-trichloro- 1,4-p1'egnadiene-1 7a,2 1-

diol-3,20-dione 17 2'-methylbutyrate) 16a,methyl-6a-fluoro-9 a,11B-dichloro-1,4-pregnadiene- 1701,21-(1101-3 ,20-dione 17-propionatel7a,21-diol-3,20-dione l7-butyrate 616a-methy1-6a-fluoro-9a,1Ill-dichloro-1,4-pregnadiene-17a,21-diol-3,20-dione 17-isobutyrate l 6a-methy1-6a-fluoro-9a,11B-dichloro-1,4-pregnadiene- 17 a,21-diol-3,20-dione 17-valerate16a-methyl-6a-fluoro-9a,1 1B-dichloro-1,4-pregnadiene-17u,21-diol-3,20-di0ne 17-is0valerate16a-methyl-6a-fluoro-9a,1IB-dichloro-1,4-pregnadienel7a,2l-diol-3,20-dione17 (2-methylbutyrate) EXAMPLE 2 6a,16a-dimethy1-9a,1Iii-dichloro-1,4-pregnadiene- 17u,21-diOl-3,20di011 17-butyrate Dissolve17.4 g. of 6a,l6a-dimethyl-9u,11}8-dichloro- 1,4 pregnadiene 17a,21 diol3,20 dione in 525 ml. of benzene. Add 17 ml. of trimethyl orthobutyrateand 0.5 g. of paratoluenesulfonic acid monohydrate. Stir the resultingsolution for /2 hour at reflux. Add 5.0 g. of solid sodium bicarbonateand 5.0 ml. of triethylamine. Stir the mixture for 15 minutes. Cool toroom temperature and filter. Concentrate the filtrate to a residueobtaining the 17,2l-methyl orthobutyrate ester of the starting material.

Dissolve the 17,2l-methyl orthobutyrate residue in 175 ml. of a aceticacid-5% water mixture with external cooling. Stir the solution at roomtemperature for 15-20 hours. Precipitate the product by the addition of10 volumes of water. Collect the precipitate on a suitable filter andwater wash it free of acid. Dry the product and crystallize fromacetone-hexane to yield the purified 611,160: dimethyl 911,116 dichloro1,4 pregnadienel7a,2l-diol-3,20-dione l7-butyrate.

By the utilization of the procedure of this example, by varying the6a-substituent on the 17a,21-diol starting material and by selecting thetri-lower alkyl ortho ester of the appropriate lower alkanoic acid,17a-lower alkanoate esters may be prepared of which the following areexemplary:

l6a-methyl-6a-fiuoro-9 a,1 Iii-dichloro-1,4-pregnadiene- :,21-di01-3,20-dione 17-propionatel6a-methyl-6a-fiuoro-9a,1lfi-dichloro-1,4-pregnadiene- 17a,21-diOl3,20-dione 17 butyrate 16a-me1hy16a-fi1.101O9oc,1lp-dichloro-1,4-pregnadiene- 17a,2 l-diol-3 ,20-dione l7-isobutyrate16a-methyl-6a-fiuoro-9a,1 1 fl-dichloro- 1,4-pregnadiene- 17a,21-di0l3,ZO-dione 17-isovalerate l6a-methyl-6a-fiuoro-9a, llfl-dichloro-1,4-pregnadiene- 17a,2 l-diol-3,20-dione 17-(2'-methylbutyrate) l6a-methyl-9a, 1'1 fi di-chloro- 1 ,4-pregnadienel7a,2 l-diol- 3 ,20-dione l7-propionate 16a-methyl-9a,1 1 fl-dichloro-1,4-pregnadiene- 17a,2 l -diol- 3 ,20-dione 17-butyrate 16u-methyl-9 a,1 lfi-di-chloro-1,4-pregnadiene-17a,21-dio1- 3 ,20dione l7-isobutyrate16a-methyl-9a,1lfi dichloro-1,4-pregnadiene-l7a,2l-diol- 3 ,20-dione17-valerate 16u-methyl-9 a,1 lpdichloro-1,4-pregnadienel 7a,2 l-diol-3,20-dione l7-isovalerate l6a-methyl-9 a,1 lfidichloro-1,4-pregnadiene-l7a,2 l-diol- 3 ,ZO-dione 17 Z-methylbutyrate)16a-m6thy1-6oc,9u, 1 l fi-trichloro- 1 ,4-pregnadiene- 17a,2 1-

diol-3,20-dione 17-propionate l6a-methyl-6a,9a,11,8-trichloro-1,4-pregnadiene-17a,21

diol-3,20-dio'ne 17-butyrate l 6a-methyl-6a,9a,1 l3-trichlo'ro-1,4-pregnadiene-17a,2 l-

diol-3,20-dione 17-is0butyrate l6a-methyl-6u,9a,llfi-trichloro-1,4-pregnadiene-l7u,2l-

diol-3,20-dione 17-valerate 16ot-I1'16thyl-6u,9a,1 lfl-trichloro- 1,4-pregnadienel7a,2 1-

diol-3,20-dione 17-isovalerate 16a-methyl-6a,9a,l 1 fi-trichloro- 1,4-pregnadiene- 17a,2 1-

idiol-3,20-dione 17- 2-methylbutyrate) 6a,16ot-dim6thy1-9m,11,3-dichloro-1,4-pregnadiene-l7a,2l-

diol-3,20-dione 17-propionate EXAMPLE 3 Dissolve 2.0 g. of 6a fluoro 16amethyl 9a,11;8-dichloro 1,4 pregnadiene l7oc,2l diol 3,20 dione 21-acetate in 20 ml. of valeric acid and 7 ml. trifluoroacetic anhydride.Heat the mixture with stirring to 80 on a steam bath. Maintain both theheating and stirring for 1 hour. Cool the reaction mixture to 50, addml. of water and stir for 10 minutes. Cool the solution to roomtemperature and pour the solution into 200 ml. of ice water withstirring. Extract the product with 50 ml. of methylene chloride. Washthe methylene chloride solution with water, with dilute sodiumbicarbonate and again with water until the extract is neutral. Dry theextract over an hydrous magnesium sulfate and concentrate the solutionto a residue. Dissolve the residue in 140 ml. of methanol, add 3.6 ml.of 70% perchloric acid and allow the mixture to remain at roomtemperature overnight (18 hours). Pour the reaction mixture into 1400ml. of a 5% salt solution with stirring. Extract the product withmethylene chloride, wash the extract neutral with water. Dry the extractover anhydrous magnesium sulfate and concentrate the solution, with theaddition of hexane, until a crystal slurry of6a-fiuoro-16a-methyl-9a,11p3-dichloro- 1,4pregnadiene-17a,2l-diol-3,20-dione 17- valerate is obtained. Chill the slurry to 0 C. andhold overnight. Fil ter and dry the product at 60 C.

In like manner, this procedure may be used on the appropriately6a-substituted 17a-hydroxy-21-acetoxy starting material to prepare:

-6ot-fluoro-16ot-methyl-9'u,llfl-dichloro 1,4pregnadienel7a,2l-diol-3,20-dione 17-propionateGot-flUOIO-16ocm6thyl-9a,1lfi-dlChlOI'O 1,4 pregnadiene- 17a-2 l -diol-3,ZO-dione 17-butyrate GOL-flUOI'O-l60t.TI16thyl-9a,1lfl-(llChlOl'O 1,4pregnadienel7u.,2l-diol-3,20-dione 17-isobutyrate6a-fluoro-16u.-methyl-9u,11 fi-dichloro 1,4 pregnadiene-17a,2l-diol-3,20-dione 17-isovalerate6a-fiuoro-16ct-methyl-9a,1lfl-dichloro 1,4 pregnadiene- 1701.,2 l-diol-3,20-dione 17- (2'methylbutyrate) 6a,16a-dimethyl-9a,1lfi-dichloro1,4 pregnadienel7m,

21-diol-3,20-dione l7-propionate 6a,l6a-dimethyl-9a,llB-dichloro 1,4pregnadiene-17ot,

2l-diol-3,20-dione l7-butyrate 6a,l6a-dimethyl-9u,l lfl-dichloro 1,4pregnadiene-17ot,

2l-diol-3,20-dione 17-isobutyrate 6a,16OL-dlmthyl-90t,11 fi-dichloro 1,4pregnadiene-lh,

21,diol-3,20-dione l7-valerate 6a,16a-dimethyl-9u,lIB-dichloro 1,4pregnadiene-l7m,

21,diol.-3,20-dione 17-is0valerate 6u,l6m-dimethyl-9u,llB-dichloro 1,4pregnadienel7ot,

2l-diol-3,20-dione l7-(2-methylbutyrate) l6a-methyl-9'a,llfi-dichloro1,4 pregnadiene-17a,2l-

diol-3,20-dione l7-propionate 16u-methyl-9a,llfi-dichloro 1,4

diol-3,20-dione 17-butyrate l6a-methyl-9a,11B-dichloro 1,4

diol-3,20 dione 17-isobutyrate 160t-InethYl-9d,1113-dlChlOl'O 1,4

diol-3,20-dione 17-va1erate l6a-methyl-9'a,1lfi-dichloro 1,4

diol-3,20-dione 17-isovalerate 16a-methyl-9c llfi-dichloro 1,4pregnadiene-l7a,2l-

diol-3,20-dione 17-(2' methy1butyrate) pregnadiene-17a,21-

pregnadiene-17a,21-

pregnadiene-l7a,21-

pregnadiene-17a,21-

6a.-Cl1l010- l 6a-methyl 9a,llfi-dichloro-1,4-pregnadienel7oc,21-dlO13,20-di0116 l7-propionate6a.-chloro-l6u-methyl 9a.,l 1fi-dichloro-1,4-pregnadienel7a,2l-diol-3,20-dione 17-butyrate6a.-chloro-16a-methyl 9a,1 lfi-dichloro-1,4-pregnadiene- ;,21-di0l-3,20-dione 17-isobutyrate 6a.-chloro-l 6a-methyl 911,1lfi-dichloro-1,4-pregnadiene- 17oz,21-dlO1-2,3 O-dione 17-valerate6a.-chloro-16a-methyl 911,1lpadichloro-1,4-pregnadienel7a,2l-dial-3,20-dione l7-isovalerate6a.-chloro- 1 6a-methyl 901,1 1 fl-dichloro-1,4-pregnadiene-17a,21-diol-3,20-dione l7-(2'methylbutyrate) The tangible embodimentsprepared in accordance with the foregoing procedures are to be utilizedin the form of pharmaceutical compositions as described hereinbelow. Itis contemplated that these embodiments may be taken orally in the formof tablets, capsules, elixirs and syrups and thereby elicit a systemicresponse. It is further in the contemplation of the applicants thatthese embodiments may be employed as topical preparations in the form ofcreams, lotions, ointments and aerosols. It is still furthercontemplated that the tangible embodiments of the instant invention bedispensed in the form of injectable compositions for intromuscular,subcutaneous and intravenous use.

The aforementioned topical formulations may optionally be of thehydrophilic or hydrophobic variety and may contain, in addition to thetangible embodiments, pigments, bacteriostatics, perfumes, anestheticsand the like. The foregoing may be included in the formulations with theproviso that they be compatible with the tangible embodiments, therebycausing no undesirable modification of the pharmacological action of theactive species.

Notwithstanding the fact that the tangible embodiments exhibit topicalantiinfiammatory activity, their principal utility is in the form oforal preparations. In this form they can best elicit the prolongedactivity which differentiates the compounds of the instant inventionfrom the steroidal antiinflammatory agents available heretofore.

The effective dosage of these compounds depends on the severity, stageand individual characteristic of each case and is appropriatelydetermined by the administering veterinarian or physician. In general,however, a dosage of from about 0.4 to about 2.0 mg. per kg. of bodyweight on a 48 hour regimen gives the desired relief. For conditionsthat may be characterized as subacute, a maintenance dose from the lowerend of the dosage scale should suffice. In fact, it is usually desirableto administer the minimum dose that will maintain the Well being of thespecies under treatment.

The following preparations are illustrative of the dosage forms in whichthe compounds of the instant invention may be employed.

Tablet-5 mg.

Mg. 16a-methyl-9a,ll 3-dichloro-l,4 pregnadiene 17a,

2l-diol-3,20-dione l7-butyrate 5.0 Starch, food grade 5.0 Lactose (spraydried) USP 89.5 Magnesium stearate 0.5

Mill the steroid to a uniform particle size and mix with the starch. Addan equal weight of lactose and blend until uniform. Transfer this blendto a larger mixing vessel, add the remainder of the lactose and blendthe mixture until homogeneous. Remove a portion of the blend 10-20 mg,blend with the magnesium stearate and add back to the steroid blend. Mixuntil uniform and compress to desired specifications.

9 Capsule mg.

6m,16a.-dlm6thy1-9a,11fi dichloro-l,4pregnadiene- 17a,21-diol-3,20-dione17-propionate 5.0 Lactose (spray dried) USP 194.5 Magnesium stearate USP0.5

Mill the steroid to a uniform, fine particle size (150- 200 mesh) andblend with approximately by 10% of the lactose in a suitable mixingvessel. Add this premix to the remainder of the lactose in a suitablemixing container and blend with the magnesium stearate until uniform anduse to fill hard shell slip capsules.

Syrup-5 mg/teaspoonful Water purified USP, to 1.0 cc.

Dissolve the steroid in the alcohol. Blend the remaining ingredients,add the steroid solution and mix until uniform. Filter the syrup usingeither filter pads or a filter aid for clarification and package theclear syrup in suitable sized bottles.

Parenteral aqueous suspension--25 mg./cc. 6a-fluoro-16-methyl-9e,1 13-dichloro-1,4- Mg. prcgn-adiene-17a,21-diol-3,20-dione 17-valerate25.00 Methylcellulose, cps., USP 0.25 Sodium citrate, dihydrate, reagent30.00

Benzyl alcohol, N.F. 9.00 Methylparaben, USP 1.80 Propylparaben, USP0.20

Water for injection, USP, to 1.00 cc.

Directions for 100 cc. formulation Charge about 45 cc. of Water to asuitably sized agitated vessel and heat to 85-90". Add themethylcellulose slowly with agitation. Add approximately 30 cc. of coldwater to the solution and coil to 8.

Dissolve the sodium citrate dihydrate in Water and add this solution tothe methylcellulose solution with stirring.

Dissolve the parabens in the benzyl alcohol at 30. Add this solution tothe sodium citrate-methyl cellulose solution and stir until uniform.

Sterilize the foregoing solution by filtration through a sterilizingfilter into a sterile receiver. Withdraw aseptically approximately 10cc. of the solution, suspend the steroid in the solution and mill theslurry to about 0.002 inch particle size. Aseptically add the milledsteroid suspension to the batch, rinse the equipment with sterile waterto the batch and adjust the volume to cc. with additional sterile water.Transfer the suspension to suitable sized sterile vials under asepticconditions.

We claim:

1. A compound selected from the group consisting of 1,4-pregnadienes ofthe formula:

wherein X is a member selected from the group hydrogen, fluorine,chlorine and methyl and R is lower alkyl having 2 to 4 carbon atoms.

2. A compound of claim 1 wherein X is hydrogen.

3. A compound of claim 1 wherein X is fluorine.

4. A compound of claim 1 wherein X is chlorine.

5. A compound of claim 1 wherein X is methyl.

6. A compound of claim 2 wherein R is n propyl, said compound being16a-methyl-9a,1lp-dichloro-lA-pregnadiene-17a,21-diol-3,20-di0ne17-b-utyrate.

7. A compound of claim 2 wherein R is isopropyl, said compound being16a-methyl-9a,11[3-dichloro-1,4-pregnadiene-17u,21-diol-3,20-dione17-iso.butyrate.

8. A pharmaceutical composition for eliciting a sustainedanti-inflammatory response in mammals comprising as the essential activeingredient a therapeutically effective quantity of a compound of claim1, in conjunction with a pharmaceutically acceptable carrier.

9. A method of eliciting a sustained anti-inflammatory response inmammals which comprises orally administering a therapeutically elfectivequantity of a composition of claim 8.

References Cited UNITED STATES PATENTS 3,201,391 8/1965 lBowers260239.55 3,236,868 2/1966 Bowers 260-397.45 3,312,590 4/1967 Elks etal. 16758 3,324,110 6/1967 Nussbaum 2602l1.5

LEWIS GOTTS, Primary Examiner.

ETHEL G. LOVE, Assistant Examiner.

US. Cl. X.R. 260239.55, 397.45

